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    Clinical Trial Results:
    Treatment of congenital vascular malformations using Sirolimus: improving quality of Life

    Summary
    EudraCT number
    		 2016-002157-38
    Trial protocol
    		 NL  
    Global end of trial date
    02 Dec 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Jun 2022
    First version publication date
    25 Jun 2022
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    57911
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03987152
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboud university medical center
    Sponsor organisation address
    Geert Grooteplein Zuid 22, Nijmegen, Netherlands, 6525 GA
    Public contact
    werkgroep@hecovan.nl, HECOVAN, werkgroep@hecovan.nl
    Scientific contact
    werkgroep@hecovan.nl, HECOVAN, werkgroep@hecovan.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Apr 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Dec 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate whether Sirolimus results in a significant and clinically relevant reduction of pain and an improved quality of life in patients with untreatable vascular malformations.
    Protection of trial subjects
    The clinical trial was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. All patients and/or their parents gave their written informed consent before any study-related procedures were undertaken. Patients were treated when (increased) pain symptoms occurred with pain relief medication for example. Adverse events were treated.
    Background therapy
    		 Cotrimoxazole as Pneumocystis jirovecii Pneumonia (PJP) prophylaxis.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 74
    Worldwide total number of subjects
    74
    EEA total number of subjects
    74
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    21
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    38
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients were enrolled at the Radboudumc between September 2017 and February 2021

    Pre-assignment
    Screening details
    		 Inclusion criteria: patients with low flow vascular malformation (venous, lymphatic or combined), aged older than 1 year, with signed informed consent. Patients who are either refractory to standard care. A run-in phase of the first three months of sirolimus use, remaining a total of 68 patients were evaluable for analysis.

    Period 1
    Period 1 title
    Screenings phase
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Screening
    Arm description
    		 Two months period of daily record of pain scores. Pain was recorded using the CHIPPS-scale, (Children and Infants Postoperative Pain Scale) for children aged 0–3 years, visual analogue scale (VAS) clinical pictures for children aged 4–7 years, VAS for patients aged 8–17 years, and numeric pain rating scale (NRS) for adults. No medication is used.
    Arm type
    		 Baseline period

    Investigational medicinal product name
    No product was used
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution in bottle
    Routes of administration
    Other use
    Dosage and administration details
    No product was used

    Number of subjects in period 1
    		Screening
    Started
    74
    Completed
    73
    Not completed
    1
         Physician decision
    1
    Period 2
    Period 2 title
    Challenge phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Challenge phase
    Arm description
    		 Six months treatment with sirolimus and co-trimoxazole profylaxis. Open-label single arm.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamune
    Pharmaceutical forms
    Tablet, Oral solution in bottle
    Routes of administration
    Oral use
    Dosage and administration details
    0.8 mg/m2 for children as start dose, 2dd1 mg as start dose for adults. Target trough levels 4-10 ng/mL

    Investigational medicinal product name
    Cotrimoxazole
    Investigational medicinal product code
    Other name
    Bactrimel, sulfamethoxazol/trimethoprim
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Children: 15/3-25/5 mg/kg/day in 1 dose, 3 times a week on consecutive days. Adults: 480 mg once per day.

    Number of subjects in period 2
    		Challenge phase
    Started
    73
    Run-in phase completion
    67
    Completed
    67
    Not completed
    6
         On patients request not complete first three month
    3
         Non-compliance
    2
         Lost to follow-up
    1
    Period 3
    Period 3 title
    Dechallenge phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Dechallenge phase
    Arm description
    		 Follow-up phase consisting of monthly phone calls
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 3
    		Dechallenge phase
    Started
    67
    Completion of Challenge phase
    67
    Completed
    67
    Period 4
    Period 4 title
    Rechallenge phase
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Rechallenge phase
    Arm description
    		 If patients experienced return of (pain)symptoms due to their vascular malformation during Dechallenge phase, patients restarted with sirolimus using low target levels of 4-10 ng/mL for a period of 12 months (Rechallenge phase).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamune
    Pharmaceutical forms
    Oral solution in bottle, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.8 mg/m2 for children as start dose, 2dd1 mg as start dose for adults. Target trough levels 4-10 ng/mL

    Investigational medicinal product name
    Cotrimoxazole
    Investigational medicinal product code
    Other name
    Bactrimel, sulfamethoxazol/trimethoprim
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Children: 15/3-25/5 mg/kg/day in 1 dose, 3 times a week on consecutive days. Adults: 480 mg once per day.

    Number of subjects in period 4 [1]
    		Rechallenge phase
    Started
    34
    Return of symptoms
    33
    Completed
    23
    Not completed
    12
         End of study
    12
    Joined
    1
         Turned to age of 1 year during study
    1
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: In total 32 patients did not restarted.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Screenings phase
    Reporting group description
    		 -

    Reporting group values
    		 Screenings phase Total
    Number of subjects
    		 74 74
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 3 3
        Children (2-11 years)
    		 21 21
        Adolescents (12-17 years)
    		 12 12
        Adults (18-64 years)
    		 38 38
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 23 ± 16.3 -
    Gender categorical
    Units: Subjects
        Female
    		 49 49
        Male
    		 25 25
    Vascular malformation type
    Units: Subjects
        Lymphatic malformation
    		 27 27
        Venous malformation
    		 33 33
        Combined malformation
    		 12 12
        Other
    		 2 2
    Mutation type
    Units: Subjects
        No mutation found
    		 9 9
        Activating PIK3CA mutation
    		 23 23
        Activating TEK mutation
    		 3 3
        Activating PTEN mutation
    		 1 1
        Activating IDH1 mutation
    		 1 1
        Combined activating mutation
    		 1 1
        Measurement failed
    		 2 2
        No DNA diagnostics done
    		 34 34
    Subject analysis sets

    Subject analysis set title
    Challenge phase
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Amount of patients who completed the Challenge phase.

    Subject analysis set title
    Children
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To investigate differences in children and adults at Baseline and after Challenge phase.

    Subject analysis set title
    Adults
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To investigate the characteristics and outcomes in adults

    Subject analysis sets values
    		 Challenge phase Children Adults
    Number of subjects
    67
    32
    35
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    3
    3
    0
        Children (2-11 years)
    18
    18
    0
        Adolescents (12-17 years)
    11
    11
    0
        Adults (18-64 years)
    35
    0
    35
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    23.3 ± 16.3
    9.5 ± 4.7
    36 ± 12.4
    Gender categorical
    Units: Subjects
        Female
    43
    23
    20
        Male
    24
    9
    15
    Vascular malformation type
    Units: Subjects
        Lymphatic malformation
    25
    16
    9
        Venous malformation
    29
    13
    16
        Combined malformation
    11
    2
    9
        Other
    2
    1
    1
    Mutation type
    Units: Subjects
        No mutation found
    9
    3
    6
        Activating PIK3CA mutation
    20
    13
    7
        Activating TEK mutation
    3
    1
    2
        Activating PTEN mutation
    1
    1
    0
        Activating IDH1 mutation
    1
    1
    0
        Combined activating mutation
    1
    0
    1
        Measurement failed
    2
    2
    0
        No DNA diagnostics done
    30
    11
    19

    End points

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    End points reporting groups
    Reporting group title
    Screening
    Reporting group description
    		 Two months period of daily record of pain scores. Pain was recorded using the CHIPPS-scale, (Children and Infants Postoperative Pain Scale) for children aged 0–3 years, visual analogue scale (VAS) clinical pictures for children aged 4–7 years, VAS for patients aged 8–17 years, and numeric pain rating scale (NRS) for adults. No medication is used.
    Reporting group title
    Challenge phase
    Reporting group description
    		 Six months treatment with sirolimus and co-trimoxazole profylaxis. Open-label single arm.
    Reporting group title
    Dechallenge phase
    Reporting group description
    		 Follow-up phase consisting of monthly phone calls
    Reporting group title
    Rechallenge phase
    Reporting group description
    		 If patients experienced return of (pain)symptoms due to their vascular malformation during Dechallenge phase, patients restarted with sirolimus using low target levels of 4-10 ng/mL for a period of 12 months (Rechallenge phase).

    Subject analysis set title
    Challenge phase
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Amount of patients who completed the Challenge phase.

    Subject analysis set title
    Children
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To investigate differences in children and adults at Baseline and after Challenge phase.

    Subject analysis set title
    Adults
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    To investigate the characteristics and outcomes in adults

    Primary: Pain reduction

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    End point title
    		 Pain reduction
    End point description
    Daily pain scores
    End point type
    Primary
    End point timeframe
    In total 8 months: 2 months of Baseline and 6 months Challenge phase
    End point values
    		 Challenge phase Children Adults
    Number of subjects analysed
    52
    32 [1]
    35 [2]
    Units: Number of responders
        Increase of pain
    2
    0
    2
        No change in pain
    0
    0
    0
        Decrease of pain
    25
    11
    14
        No pain due to VM
    13
    14
    17
        No (complete) dairy
    12
    7
    1
    Notes
    [1] - Responded children and completed dairy
    [2] - Responded adults and completed dairy
    Statistical analysis title
    		 Daily pain scores
    Comparison groups
    Children v Adults
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Return of pain(symptoms)

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    End point title
    		 Return of pain(symptoms)
    End point description
    Monthly phone calls, if level of pain or symptoms related to the vascular malformation returned to the level of baseline.
    End point type
    Secondary
    End point timeframe
    During 12 months follow-up visit
    End point values
    		 Dechallenge phase Children Adults
    Number of subjects analysed
    44
    25
    19
    Units: Number of responded patients
        No recurrence of symptoms
    37
    3
    4
        Recurrence of symtpoms
    7
    22
    15
    Statistical analysis title
    		 Recurrence of pain
    Statistical analysis description
    Differences between children and adults in terms of recurrence of symptoms.
    Comparison groups
    Children v Adults
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Reduction of malformation size

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    End point title
    		 Reduction of malformation size
    End point description
    MRI at baseline was compared with MRI at end of Challenge
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Challenge phase Children Adults
    Number of subjects analysed
    62 [3]
    32
    35
    Units: amount of patients
        Decrease of volume
    22
    12
    10
        No change
    38
    19
    19
        Increase of volume
    2
    0
    2
    Notes
    [3] - In total 5 patients had no MRI
    Statistical analysis title
    		 Differences in change volume per child/adult
    Comparison groups
    Children v Adults
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Chi-squared
    Confidence interval

    Secondary: Genetic factors

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    End point title
    		 Genetic factors
    End point description
    During Challenge phase, respons after six months
    End point type
    Secondary
    End point timeframe
    6 months
    End point values
    		 Challenge phase Children Adults
    Number of subjects analysed
    20 [4]
    13
    7
    Units: amount responders with PIK3CA mutation
        Responder
    14
    11
    3
        No responder
    6
    2
    4
    Notes
    [4] - In all patients with a PIK3mutation
    Statistical analysis title
    		 Differences in PIK3CA mutation and children adults
    Comparison groups
    Children v Adults
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 ≤ 0.05
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Since start of Challenge phase untill end of study.
    Adverse event reporting additional description
    Adverse events were reported and assessed according to the Common Terminology Criteria for Adverse Events 4.03.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Included patients
    Reporting group description
    		 -

    Serious adverse events
    		 Included patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 74 (13.51%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Laboratory test abnormal
    Additional description: Increased liver enzymes, decreased phosphate
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Bleeding
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiration abnormal
    Additional description: Hypoxic arrest, pneumonia, sinusitis
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    4 / 5
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection
    Additional description: Sepsis, viral infections, cellulitis
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    4 / 6
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Included patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 74 (100.00%)
    Investigations
    Laboratory test abnormal
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    23 / 74 (31.08%)
         occurrences all number
    31
    Nervous system disorders
    Headache
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    27 / 74 (36.49%)
         occurrences all number
    45
    Blood and lymphatic system disorders
    Neutropenia
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences all number
    11
    General disorders and administration site conditions
    Fatigue
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    26 / 74 (35.14%)
         occurrences all number
    35
    Immune system disorders
    Leukopenia
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Gastrointestinal disorders
    Abdominal pain
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    16
    Aphtosous
    Additional description: Independent of relationship with sirolimus
         subjects affected / exposed
    44 / 74 (59.46%)
         occurrences all number
    64
    Diarrhoea
    Additional description: Independent of relationship with sirolimus
         subjects affected / exposed
    12 / 74 (16.22%)
         occurrences all number
    14
    Gastroenteritis
    Additional description: Independent of relationship with sirolimus
         subjects affected / exposed
    18 / 74 (24.32%)
         occurrences all number
    21
    Nausea
         subjects affected / exposed
    12 / 74 (16.22%)
         occurrences all number
    12
    Respiratory, thoracic and mediastinal disorders
    Upper respiratory tract infection
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    40 / 74 (54.05%)
         occurrences all number
    69
    Skin and subcutaneous tissue disorders
    Erythema
    Additional description: Erythematous eruption with papules, acnei forme eruption Independed of relationship with sirolimus
         subjects affected / exposed
    12 / 74 (16.22%)
         occurrences all number
    18
    Xerosis
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    9
    Oedema
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    9
    Endocrine disorders
    Menstrual disorder
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    11
    Musculoskeletal and connective tissue disorders
    Myalgia
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    8
    Infections and infestations
    Infection
    Additional description: Independed of relationship with sirolimus
         subjects affected / exposed
    50 / 74 (67.57%)
         occurrences all number
    64
    Metabolism and nutrition disorders
    Appetite disorder
    Additional description: Decreased appetite - independed of relationship with sirolimus
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Mar 2019
    Due to the high quantity of children with low flow malformations, the number of children included will be higher. Instead of 20 children a maximum of 35 children will be inlcuded. Minor changes have been made by the protocol to (correct errors and/or) improve the overall clarity of the original protocol. These adjustments do not affect the safety, exposure or overall study design.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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